JPH03501725A - Thienotricyclen for the treatment of bronchial diseases - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Fields of application of the invention of thienotrizyclen for the treatment of bronchial diseases The present invention relates to dihydrochenobenzodia for the manufacture of a medicament for the treatment of bronchial diseases. A new use of Zepinone, this enantiomerically pure form of dihydrochenobenzodiazepinone, The present invention relates to its manufacturing method and its uses.

Known technical background Dihydrochenobenzodiazepinone and Its use for the treatment of gastric or intestinal diseases is known. More dibenzodia Zepinone and pyrido-benzodiazepinone exist in chiral conformations that are mirror images of each other. It is known that conformational isomer mixtures exist in a given case, i.e. Depending on the situation, it can be separated into optical mirror images (West German patent application published No. 3531682 specification).

Description of the invention Described in European Patent No. 0039519 I; Dihydrochenobenzodiaze Pinone, the compound 4゜9-dihydro-3-methyl-4-[(4-methyl-1 -piperazinyl)acetyl]-10H-cheno[3゜4-bl　[1,5]be Nzodiazepine-1o-one (INN: telenzepine) has unexpectedly excellent bronchial effects. It was found to exhibit antispasmodic properties. Furthermore, appropriately substituted I; Nobenzodiazepinones, especially telenzepine, can be easily and in high yields optically synthesized. A method has been found that allows separation into enantiomeric forms.

Therefore, the subject of the invention is the manufacture of medicaments for the treatment and prevention of bronchial diseases. 4,9-dihydro-3-methyl-4-[(4-methyl-1-piperazinyl) ) acetyl]-10H-cheno[3,4-bl][1,51 benzodiazepine -10-one and its pharmacologically acceptable salts.

Another subject of the invention is the manufacture of medicaments for the treatment and prevention of bronchial diseases. The (+)-enantiomer of telenzepine, i.e. (+)-4,9-dihydro- 3-Methyl-4-((4-methyl-1-piperazinyl)acetyl]-10H-thi eno[3,4-bl][1,51 benzodiazepine-10-one and its drugs Uses of physically acceptable salts.

Another subject of the invention is the compound (+)-4°9-dihydro-3-methyl- 4-[(4-methyl-1-piperazinyl)acetyl]-10H-cheno [3゜ 4-bl　N,5]benzodiazepine-10-one and/or its pharmacological It is a medicine containing a salt that is tolerated by.

As a salt, it is advantageous in this connection to combine pharmacologically with the pharmaceutically common inorganic and organic acids. Includes tolerable salts. For example, fumaric acid (7 malate), tartaric acid (tartaric acid) salts) or maleic acid (maleate). Advantageous acid addition Examples of salts include dihydrochloride.

This medicament can be produced by known methods, in which case the compound alone or tablets, dragees, optionally in combination with suitable pharmaceutical auxiliaries or carriers. , capsules, suppositories, soft IF (e.g. TTS), emulsions, suspensions, Used in azole or solution form. New pharmacological preparations can be used in addition to active substances With pharmacological carriers, the active substance content of this mixture ranges from 0.5 to 0.5 of the total mixture. 95% by weight, preferably 15-75% by weight.

The person skilled in the art will know which auxiliaries or carriers are suitable for the desired pharmaceutical preparation. It is well known based on professional knowledge. Solvents, gel-forming agents, herbal drug bases, tablet-auxiliary agents and the like In addition to other active substance carriers, e.g. antioxidants, dispersants, solubilizers, colorants, etc. In particular, the use of penetration aids and complexing agents (e.g. cyclodextrin) You may.

This medicinal product ensures the formation or maintenance of sufficient blood concentrations of the active substance. As a prerequisite, they can be applied in each case in the form of suitable preparations. This is an analogy For example, it can be achieved by oral or parenteral administration at an appropriate dose. usually , the pharmaceutical preparation of the active substance is present in the form of a unit dose, and this unit dose is It can be adjusted to the administration of Wataru. One unit dose is e.g. rice tablets, sugar-coated tablets. , capsules, layers or powders, granules, solutions, emulsions or ; is a suspension.

A “unit dose” in the sense of the present invention refers to A physically constant unit containing the individual amounts of the active ingredient used in the active ingredient. Amounts correspond to fractions or multiples of individual dosage units for therapeutic use. The unit dose is All, half, third, or quarter of the daily dose given at the time of use and usually It is advantageous to include an amount of active substance corresponding to .

For individual therapeutic administrations, such as half or quarter of this unit dose. If a fractional fraction is required, this unit dose may be used, for example, in the form of a tablet with notches. It is advantageous that it can be divided.

This pharmacological preparation according to the invention may be present in unit dosages and e.g. When intended for administration to humans, the amount of active substance 0.1-1 Omg, advantageously It can also contain 0.5 to 5 mg, especially 1 to 4 mg.

Therapeutic administration of the pharmacological preparation is from 1 to 4 times per - day, at regular intervals or at varying times. For example, before meals and/or in the evening, respectively. but necessary case, i.e. type of individual to be treated, weight and age, type and severity of disease; , the type of preparation, the application of the drug, and the time or interval of administration. may be removed from the administration. Thus in some cases less than the above amount It is possible to get away with a smaller amount of active substance, but in other cases, the amount of active substance must be surpassed. Relatively high doses administered at the beginning of treatment in emergency cases be done. After the desired effect has occurred, the lower dosage is returned.

Determination of the respective necessary optimal dosage and application method of the agent is within the skill of the respective person skilled in the art. can be done based on that knowledge.

Pharmacological preparations usually contain an active substance and a non-toxic, pharmacologically acceptable pharmaceutical carrier. The carrier consists of admixtures and diluents in solid, semi-solid and liquid form. or as coatings in the form of capsules, tablet jackets, sacks and cases, used. This carrier can be used, for example, as an aid for drug absorption into the body. As a formulation aid, as a sweetener, as a flavoring agent, as a coloring agent or as a preservative. It is used as

For oral administration, e.g. tablets, dragees, hard and Soft capsules, dispersible powders, granules, aqueous or oily suspensions, emulsicone , solutions or syrups can be used.

Tablets are prepared with inert diluents such as calcium carbonate, calcium phosphate, phosphoric acid Sodium or lactose; granulating or dispersing agents such as cornstarch or or alginates; binders such as starch, gelatin or gum arabic; and lubricants such as aluminum stearate and magnesium stearate. talc or silicone oil. This tablet is additionally coated. This may lead to delayed dissolution and absorption of the drug in the gastrointestinal tract. For example, better compatibility, long-lasting properties Or delay can be achieved. Gelatin capsules are solid diluents e.g. Calcium carbonate or kaolin or oily diluents such as olive oil, lacquer It may contain sesame oil and paraffin oil.

In some cases, aqueous suspensions prepared over short periods of time may contain suspending agents such as sodium calcium. Boxymethylcellulose, methylcellulose, hydroxypropylcellulose, Sodium alginate, polyvinylpyrrolidone, gum tragacanth or arabic Agums; dispersants and wetting agents such as polyoxyethylene stearate, hepta Decaethylene oxycetanol, polyoxyethylene sorbitol monooleate polyoxyethylene sorbitan monooleate or lecithin; preservatives and e.g. methyl- or propyl hydroxybenzoate; flavoring agents; sweeteners e.g. Sucrose, lactose, sodium cyclamate, dextrose, invert sugar May contain syrup.

Oily suspensions are suitable; for example peanut oil, olive oil, sesame oil, coconut oil or paraffin oil and beeswax, hard paraffin; cetyl alcohol; and It may also contain sweeteners, flavoring agents and antioxidants.

Water-dispersible powders and granules contain medicinal substances as dispersants, wetting agents and suspending agents. Mixed with clouding agents, such as those mentioned above, as well as sweetening, flavoring and coloring agents. It may also be contained.

The emulsion contains emulsifiers, gum arabic, gum tragacanth, phospholipids, and sorbita. In addition to polyoxyethylene sorbitan monooleate and polyoxyethylene sorbitan monooleate, Contains leave oil, peanut oil or paraffin oil, and sweeteners and flavoring agents You may.

To apply medicinal substances to the rectum, a herbal preparation is used, which dissolves at rectal temperature. Made with a melting binder, such as cocoa butter or polyethylene glycol. will be built.

Sterile injectable, sometimes quick-to-manufacture products for pharmacological applications of medicinal substances. aqueous suspension, saline or dispersing or wetting agent and/or pharmaceutical a diluent that is acceptable to the public, such as propylene glycol or butylene glycol. Other solutions containing .

Oral application of medicinal substances is advantageous.

Advantageous for application as a bronchial spasmolytic agent is the adult application of the active substance.

It can be applied either as a powder [in contact with it] or as a spray of a solution or suspension containing the active substance. administered by. In this case, this atomization is carried out in the usual way, for example by compressed air atomization. It can be carried out using an ultrasonic nebulizer or an ultrasonic nebulizer. Injection metering, especially traditional injection It is particularly advantageous to administer from a device with a metering valve (metered aerosol). Ru. With metered aerosols, a constant amount of active substance is delivered per - injection. Can be supplied. Particularly advantageous here are so-called simultaneous aspirators, which Administration of the active substance can take place at the same time. A suitable simultaneous-suction device is West German Patent No. 1945257, West German Patent No. 1917911 and West German Patent No. It is disclosed in Japanese Patent Publication No. 2055734.

For inhalation purposes, the active substance is advantageously administered in micron form. Particle sizes of less than 10 μm are preferred. For dosing from a spray meter In addition, the active substance is dispersed in conventional propellants, preferably using dispersants. promotion In particular, trichlorofluoromethane (Frigen@l 1) and di- A mixture of chlorodifluoromethane (Frigen 12) may be mentioned. that time , trichlorofluoromethane in whole or in part 1.1.2. - trichlorotri It may be replaced with fluoroethane (Frigen” 113).Dispersant In particular, the commonly used sorbitan ester (5pane・At1as) is used for this purpose. GmbH) and lecithin. This dispersant is difficult to exist when cooled. Dissolved in volatile propulsion components. The micronized active substance is stirred in this solution. be done. This dispersion is placed in a spray can. Crimp f: (Vercri+ After ++pan), the easily volatile propellant component is press-fitted.

The active substance is optionally combined with one or more of the carriers or additives mentioned above. It may also be prepared in the form of microcapsules.

Bronchial diseases of various origins in humans or animals (e.g. bronchitis, bronchial asthma), e.g. chronic abstruktiv airway Examples include diseases. These are combined with telenzevin or (+)-telenzepine. can also be treated based on its excellent bronchial antispasmodic properties. The subject of the present invention is It is a method of treating bronchial diseases in mammals, especially humans. This method is used to treat bronchial diseases. The affected individual is given therapeutically effective and pharmacologically tolerated doses of telenzebin and (+ ) - characterized by the administration of telenzevin.

Telenzepine is known from EP 0 039 519. telenzepi The (+)-enantiomer of the Ru. Enantiomeric separation disclosed in German Patent Application No. 35 31 682 cannot show excitation through diastereomeric salts, but this method Lenzevin (compound of formula I) as such or in deprotonated form, Represented by formula 11 [wherein R represents a chiral group of the configuration unit and X represents a leaving group] A diastereomer mixture 111 obtained by reacting with a chiral compound having a configuration unit of and liberate the conformational unit of Compound I from the optically pure diastereomer. It is characterized by

formula! In principle, compounds with all chiral configuration units can be mentioned as compounds under ■. ,Compound! Or to react while separating the leaving group X with its anion. This group R can be easily and undesirably separated by diastereomeric separation. It can be divided arbitrarily.

As leaving group X, in particular all nuclear atoms or groups, t; for example halogen atoms (+ , BrI; is Cl2) or activated by esterification, e.g. with sulfonic acid. modified hydroxyl group (-0-502-CHs, -0-502-CF3 or -0-3O2-C6H4-1)-CH3 is obtained.

As radicals R, mention may be made of all the radicals of conformational units, which may be naturally or synthetically chiralized. can be derived from compounds that are solvolytically mild, advantageously mildly acidic can be resolved from compound II+ under the conditions of

As radicals R, mention may be made in particular of the following:

derived from glycopyranose, glycofuranose or oligosaccharides and the desired In carbohydrate chemistry, common protecting groups can partially or completely protect A glycosyl group, or a chiral, terpene alcohol group linked through an oxygen, or other chiral, alcohol groups bonded through oxygen, each of which is a bonding atom The carbonyl group or I bonded to the oxygen atom functioning as a group is particularly one having a methylene group. do.

Preferred radicals R are of the formula IV R1-0-CH2-(IV) [In the formula, R1 together with the oxygen atom bonded to this represents a glycosyl group, a chiral represents a terpene alcohol group or other chiral alcohol group] This is the base.

As glyphcyl group R1-0-C)12, for example natural mono- or disaccharides can be used. For example arabinose, fructose, galactose, glucose, lactose , mannose, lipose, xylose, maltose, sorbose or N-acetate Examples include groups derived from tyl-D-glucoseamine.

Chiral terpene alcohol groups, especially natural ones, can be easily obtained by synthesis. Examples include groups derived from terpene alcohols. For example, tell As pen alcohols, mention may be made in this case of: impregrol, net Omenthol, immenthol, menthol, carveol, dihydrocarveo ol, terpinen-4-ol, myrtenol, citronellol, isoborneol ole, borneol, 7-enfur and especially isobinocampheol.

Other chiral alcohol groups R1-0- can be derived from, for example, the following alcohols: Examples of derived groups include: mandelic acid ester, quinconidine, quinfunin, Phedrine, serine methyl ester 3-hydro-2-methyl-propionic acid methyl ester and ethyl lactate Stell.

A particularly preferred radical R is the impinocamphenyloxymethyl radical.

Compound early summer and compound ■! The reaction with is carried out by methods known to those skilled in the art. Core of compound I It is preferable to deprotonate it in order to increase its properties. As a deprotonating agent, Common bases used in organic chemistry can be used for similar reactions. . Examples of this include hydroxides, I; for example sodium hydroxide or potassium hydroxide, or or carbonates, such as potassium carbonate, or alcoholades, such as sodium methylate or sodium nittylate, or amines such as pyridine, triethylamine or ethyldiisopropylamine, or organometallic compounds, For example, t-butyllithium or t; is preferably a hydride such as sodium hydride. It is mu.

Deprotonation of compound l and subsequent compound ■! The reaction with It is carried out in an inert protic or aprotic solvent, depending on the case. like this Examples include methanol, impropanol, dimethyl sulfoxide, Acetone, acetonitrile, dioxane and preferably dimethylformamide are suitable. Depending on the reactivity of the deprotonating agent, the deprotonation of compound It is carried out at temperatures of up to +100°C, in particular at temperatures of up to +100°C. continue , the reaction of deprotonated compound I with compound 11 avoids undesirable side reactions. In order to With summer! Separation of the diastereomers obtained from the reaction with t; for example by chromatography on a suitable column, preferably by fractional distillation.

When separation is carried out by crystallization, the diastereomers obtained can be separated using a suitable method. It is advantageous to convert it into a crystallizing salt. For example, Oxale Suitable are salts, tosylates, fumarates and especially maleates.

Separation of compounds il+ from these salts by efficient diastereomeric separation is suitable. This is done using a base that is not too strong. For this reason, e.g. bicarbonate, e.g. Sodium oxyhydrogen is suitable.

Separation of the conformational units of Compound I from optically pure diastereomers is accomplished by solubilization. It is carried out under mild, slightly acidic conditions. As a reagent suitable for soluble solvent decomposition Examples include adding hydrochloric acid and formic acid anhydride.

Compounds of formula I+ are known or can be prepared from known compounds by methods known to those skilled in the art. can be obtained in a similar manner. Thus, for example, compound I+ [wherein R is In formula IV, t represents a compound, X represents a chlorine atom] represents the corresponding alcohol can be produced by chloromethylation of [e.g. Analogiez u R. C. Ronald et al, J, Org. Chem. 45 (1980) 2224].

The conformational unit of compound l obtained by separation from the optically pure diastereomer (this This is linearly polarized light with a wavelength of 589 nm rotating in one direction (+) or (-). , that is, (+)-4,9-dihydro-3-methyl-4-[(4-methyl-l-pi perazinyl)-acetyl]-10H-cheno-[3.4-bl　[1.51ben Zodiazepine-lO-one and (-)-4,9-dihydro-3-methyl-4- [(4-Methyl-l-piperazinyl)-acetyl]-10H-cheno-[3.4 -bl [1.51 Benzodiazepine-lO-one and its salts have unexpected pharmacological properties It is a new compound with chemical properties.

Therefore, another subject of the invention is (+)-4,9-dihydro-3-methyl -4-[(4-methyl-1-piperazinyl)-acetyl 1-10H-cheno- [3.4-bl N. 5] Benzodiazepine-10-one and its salt.

Similarly, (-)-4,9-dihydro-3-methyl-4-[(4-methyl-1-pi perazinyl)-acetylgo 10H-thieno-[3,4-bl　[1,51ben Zodiazepin-10-one and its salts are also a subject of the invention.

Advantageously in this connection, as a salt, it can be used pharmacologically with pharmaceutically common inorganic and organic acids. Scientifically acceptable salts may be mentioned. Preferred acid addition salts include dihydrochloride. It will be done.

Another subject of the invention is the method according to the invention, which is represented as an intermediate. is a compound of formula I11 [wherein R represents the above-mentioned] and salts thereof .

[Example〕 Next, the present invention will be explained in detail with reference to Examples, which are not intended to limit the present invention. stomach.

Example 1 4.9-dihydro-9-[(+)-isopinocane7yloxymethyl]-3- Methyl-4-[(4-methyl-1-piperazinyl)-acetylgor 10H-thie No[3,4-blN,5]benzodiazepine-1O-one 4.9-dihydro-3-methyl-4-[(4-methyl-1-piperazinyl)-a Cetylgo 10H-thieno-[3,4-bl [1,5]benzodiazepine-1 109.6g of 0-one was mixed with 2.2Ω of water-free dimethylformamide under nitrogen atmosphere. and warmed to 40°C. 14.2g of sodium hydride in 2.5 hours (80% suspension in paraffin oil) was added under stirring. Continue with this mixture was stirred at room temperature for 16 hours. After that, it was cooled to +5°C and the (+)-iso Pinocan 7-Eyl Chloromethyl Ether Add t;. The mixture was stirred for a further 30 minutes at 5°C, followed by 150 g of glacial acetic acid. mff was added. The solution was concentrated on a rotary evaporator. Add the remainder to 300rrl of water. Melted. The solution was first adjusted to pH 1-2 with 2N MCI2. After 5 minutes, Solid sodium bicarbonate was added until the pH value reached 9. Acetate ester 3 Extract with 200 ml of 97.0 g of manufactured product was obtained. Purification was performed by silica gel chromatography. Ta. (Bulking agent: toluene/dioxane/methanol-7o:is:15). the purpose Compound 76, 1 g (69%), was isolated as a colorless, amorphous solid. ([ α]”2-+25.

2'); c-+dichloromethane/methanol l=1).

Example 2 4,9-dihydro-9-[(-)-isopinocampheyloxymethyl]-3- Methyl-4-[(4-methyl-1-piperazinyl)-acetyl]-108-che ノ [3.4-bl N. 5] Benzodiazepine-10-one 4,9-dihydro-3-methyl-4-[(4-methyl -l-piperazinyl)-acetyl]-10H-cheno [3.4-bl[l .

5] 10.0 g of benzodiazepine-lO-one and (-)-isopinocampheil -Starting from 4.1 g of chloromethyl ether, 6.3 g of the target compound was obtained in a colorless amorphous form. Isolated as a solid. ([al　”--23-　1”　;　c””　1　+ dichloromethane/methanol-1:1).

Example 3 (+)-4.9-dihydro-9・-[(+)-isopinocampheyloxymethylene ]-3-methyl-4-[(4-methyl-1-piperazinyl)-acetylgo 1 OH-thieno [3.4-bl [1.51 benzodiazepine-1O-on-ma] Reate 4,9-dihydro-9-[(+)-isopinocampheyloxymethyl]-3- Methyl-4-[(4-methyl-1-piperazinyl)-acetyl]-10H-thiodi No [3.4-bl [1.5] benzodiazepine-10-one 76,0g and Dissolve 16.4 g of maleic acid in 1.51 g of ethanol while warming (to 70°C). Ta. From this solution after 16 hours at room temperature and 1 hour at +10°C, the target compound 19 ．． 2g (20%) crystallized. Melting point = 205℃; ([σ] 22-+98.2 6 i””l, dichloromethane/methanol-1:l).

Example 4 (-)-4.9-dihydro-9-[(-)-isopinocampheyloxymethyl 1-3-Methyl-4-[(4-methyl-1-piperazinyl)-acetylgo 10 H-thieno[3,4-bl[1.5]benzodiazepine-lO-on-mer Reate 4,9-dihydro-9-[(-)-isopinocane7yloxymethyl]-3- Methyl-4-[(4-methyl-1-piperazinyl)-acetyl]-10H-thiodi ノ [3. 4-bl [1,5]benzodiazepine-1O-one 5.8g and 1.25 g of maleic acid was dissolved in 140 ml of ethanol. From this solution the chamber After 16 h at room temperature and 1 h at 0 °C, the diastereomeric mixture ([al22 --77'; c-1. 2.1 g of dichloromethane/methanol-1:1) I put it out. 1.8 g of this mixture was recrystallized in 30 ml of ethanol.

850 mg (14%) of the target compound was isolated as colorless crystals. Melting point: 207°C.

([ffl 22--96.4"; c = 1 + dichloromethane/meth Norru 1:l).

Example 5 (4-Methyl-1-piperazinyl)-acetylgo-10H-thieno [3. 4 -bl　[1.51Benzodiazepine-lO-one (+)-4,9-dihydro-9-[(+)-isopinocampheyloxymethyl 1-3-methyl-4-[(4-methyl-1-piperazinyl)-acetyl]-10 H-cheno (3,4-bl [1,5]benzodiazepine-1O-one-male Eight 10. Suspend Og in 100ml of water and add 1.4g of sodium hydrogen carbonate. added. This solution was extracted with 3×100 ml of acetate I:. sulfur organic extract The mixture was dried over sodium chloride and subsequently concentrated. 8.1g (99%) of target compound Isolated as a colored amorphous solid. ([ff122-+96.1"Hc = 1 + Dichloromethane/methanol-1:l).

Example 6 (-)-4,9-dihydro-9-[(-)-isopinocampheyloxymethyl 1-3-methyl-4-[(4-methyl-1-piperazinyl)-acetyl]-10 H-cheno[3,4-bl[1,5]benzodiazepin-10-one By the method described in Example 5, (-)-4,9-dihydro-9-[(-)-isopi 7-ethyloxymethyl]-3-methyl-4-[(4-methyl-1-pipera [dinyl)-acetyl]-10H-cheno[3,4-bl[l,5]benzodia 700 g of zepin-10-one-maleate and 200 mg of sodium bicarbonate reacted. 550 mg (96%) of the target compound was isolated as a colorless amorphous solid. did. ([6]"2-+96°6°; awl, dichloromethane/methanol- 1:1).

Example 7 (+)-4,9-dihydro-3-methyl-4-[(4-methyl-1-piperazine )-acetyl]-10H-cheno[3,4-bl[1,5]benzodiaze pin-10-on (+)-4,9-dihydro-9-[(+)-isopinocampheyloxymethyl ]-3-Methyl-4-[(4-methyl-1-piperazinyl)-acetyl 1-1O 6.6 g of H-cheno[3,4-N N,5]benzodiazepine-1O-one Formic acid with hydrogen chloride added at room temperature (pass dry hydrogen chloride gas through formic acid for 5 minutes at room temperature) ::) It was dissolved in 66m4. After 5 minutes, the solvent was distilled off using a rotary evaporator and the residue was dissolved in water. It takes 100m12. Adjust this solution to pH 1-2 with 2N MCI2 and then The mixture was extracted with 3×50 mQ of dichloromethane. Subsequently, the aqueous phase is diluted with sodium bicarbonate. The pH was adjusted to 9 using dichloromethane and extracted with 3×100 m4 of dichloromethane. Sodium irate After drying, the organic extracts were concentrated. Chromatography of the residue on silica gel Purified by (Developing agent: toluene/dioxane/methanol-70:15715) did. 3.5 g (67%) of the target compound was isolated as a colorless amorphous solid. ([a l 22-+41.2° HC-1+dichloro 4°; c-1, chloroform 12 dihydrochloride (2HCI X 1.I H2O) has a melting point (decomposition) of 223-229°C; [irl 22-+ 26.4°; C-1; water).

Example 8 (-)-4,9-dihydro-3-methyl-4-[(4-methyl-1-piperazine )-acetyl]-10H-cheno[3,4-bl[1,5]benzodiaze Pin-1O-on (-)-4,9-dihydro-9-((-)-isopinocampheyloxymethyl ]-'3-Methyl-4-[(4-methyl-1-piperazinyl)-acetyl]-1 0H-cheno[3゜4-bl　N,5]benzodiazepine-10-one 400 mg was reacted in formic acid/HCQ4mO and purified as described in Example 7. . 250 mg (90%) of the desired compound was isolated as a colorless amorphous solid. ([al 22=-41, 0″’; c-1+ dichloromethane/methanol-1: l ; [ffl 22--32.5"; c-1, chloroform; this dihydroc Lolide (2HCQXH20) has a melting point (decomposition) of 223-229°C; [ rl 22--26.3"; c-1; water).

Industrial applicability Compound 4.9-dihydro-3-methyl-4-[(4-methyl-1-piperazinyl ) acetyl]-10H-thio[3,4-bl　[1,51benzodiazepine-1 0-one and (+)-4,9-dihydro-3-methyl-4-((4-methyl -1-piperazinyl)acetyl]-10H-cheno[3,4-b]benzodi Azepin-10-one and its pharmacologically acceptable salts are novel, hitherto unknown compounds. It exhibits pharmacological effects, and this effect makes this compound industrially applicable. This transformation The compound has proven to be highly effective for the treatment of bronchial diseases and is therefore It is particularly suitable for use in medicine and veterinary medicine.

The excellent bronchotherapeutic properties of both compounds are particularly expressed in terms of their excellent bronchial spasmolytic activity. It will be done. This bronchial spasmolytic activity can be observed with very small doses. Ru. In this connection, high specificity, i, v, - occurring continuously and multiple times after injection. The mild effect and the particularly long-lasting bronchial antispasmodic action are particularly desirable. and the substance is outstandingly suitable for the treatment of asthma diseases and exhibits the above-mentioned effects; In this case, due to the unexpectedly long duration of action, this substance may be Used to treat breath attacks.

This remarkable advantage occurs without significant side effects and does not significantly affect the cardiovascular system. t; in terms of efficacy, this compound (±)-telenzepine and (+)-telenzepine is clearly superior to the bronchial antispasmodics known from the prior art. (±) − Terene Zevin and (+)-telenzevin are the only compounds to date with this type of action. It shows good effects when administered intraarterially, intrabronchially (i, t,) and even orally. That is excellent.

Furthermore, the compound (+)-4,9-dihydro-3-methyl-4-[(4-methyl- 1-perazinyl)-acetylgo 10H-thieno [3,4-bI [1,5] Benzodiazepine-IO-ones have demonstrated significantly potent antimuscarinic effects. , this compound has been used in medicine and medicine due to its excellent anti-heel ulcer and gastric acid secretion inhibiting properties. It is particularly suitable for use in veterinary medicine. Unexpectedly this (+) -4,9 -dihydro-3-methyl-4-[(4-methyl-1-berazinyl)-acetyl] -1OH-cheno[3,4-bl　[1,5]benzodiazepine-10-one is , (-)-4,9-dihydro- 3-Methyl-4-[(4-methyl-1-berazinyl)-acetylgo-10H-thi significantly more than eno[3,4-bl[1,5]benzodiazepine-10-one Shows excellent muscarinic antagonistic properties.

Compound (+)-4,9-dihydro-3-methyl-4-[(4-methyl-1-pera (dinyl)-acetyl 1-10H-cheno[3,4-bI El,5]benzodi Azepin-1O-one clearly suppresses gastric acid secretion in warm-blooded animals and also inhibits gastric acid secretion in warm-blooded animals. It exhibits excellent gastric and intestinal protective effects in foods. This gastro- and intestinal-protective effect is already Already observed with administration of doses below those that suppress acid secretion. Further compounding (+)-4,9-dihydro-3-methyl-4-[(4-methyl-1-berazine )-acetylgo-10H-thieno [3,4-bl N,5]benzodiazepi N-10-one is superior due to its lack of significant side effects and wide therapeutic use. Ru.

This "stomach and intestinal protection" refers to gastrointestinal diseases, especially gastroenteritis and and disorders (e.g., gastric ulcers, duodenal ulcers, gastritis, hyperacid or drug-induced stinging). prevention and treatment of inflammatory gastrointestinal disorders, such as microorganisms, bacteria, pharmaceuticals (t ; e.g. anti-inflammatory and anti-rheumatic agents), chemicals (e.g. ethanol), stomach acid. or caused by stress conditions.

In this excellent property, the compound (+)-4,9-dihydro-3-methyl-4- [(4-Methyl-1-berazinyl)-acetylgo-10H-thieno [3,4- bIN,5+]benzodiazepine-10-one was unexpectedly found in the prior art (European The conformational mixture known from Patent No. 0039519), i.e. (±)-4,9 -dihydro-3-methyl-4-[(4-methyl-1-perazinyl)-acetyl] -10H-cheno [3,4-bI [1,5]benzodiazepine-10-o It has been proven to be superior to Based on this property, the (+)-conformer and Pharmacologically acceptable salts are recommended for gastric and intestinal diseases and significantly elevated gastric acid secretion. For use in humans or warm-blooded animals for the treatment and/or prevention of diseases such as It is especially good for

Therefore, another subject of the invention is gastric and intestinal diseases and markedly elevated stomach acid. Compounds for application in the treatment and/or prevention of secretion-based diseases (+)-4,9-dihydro-3-methyl-4-[(4-methyl-1-perazinyl )-acetylgo 10H-thieno [3,4-bl [1,5]benzodiazepi It is 10-one.

Similarly, the present invention provides compound (+)-4,9-dihydro-3-methyl-4-[( 4-me≠ru-1-perazinyl)-acetylgo 10H-thieno[3,4-bl [l,5]benzodiazepine-1O-ones are associated with gastric and intestinal diseases and markedly elevated Uses for the treatment and/or prevention of diseases based on gastric acid secretion It is.

Compound (+)-4,9-dihydro-3-methyl-4-[(4-methyl-1-pera (dinyl)-acetylgo-10H-thieno[3,4-bl[1,5]benzodi Azepin-IO-one and/or its salts can be used to treat gastric and intestinal diseases and severe It may be used for the treatment and/or prevention of diseases based on high gastric acid secretion. If the pharmaceutical preparation is intended to contain one or more drugs of other types, Chemically active ingredients, such as antacids, such as aluminum hydroxide, aluminate mag nesium; acid secretion inhibitor; t; for example, H2-blocker (for example, cimetidine); , ranitidine); tranquilizers; e.g. benzodiazepines; e.g. Azepam; antispasmodic agents such as Bietamiverin, Camylofin, anticholinergic agent; for example, oxyphency Oxyphencyclimin, Phencarbamide carbamide; local anesthetics such as Tetracaine; ), Procaine; in some cases, enzymes, vitamins or amino acids It may also contain amino acids. This compound (+)-4,9-dihydro-3-methyl- 4-[(4-methyl-1-berazinyl)-acetylgo 10H-thieno [3, 4-bl [1,5]benzodiazepine-10-one further helps prevent gastrointestinal diseases. for the purpose of antagonizing its ulcer performance and reducing such side effects. It may also be used in combination with substances such as anti-inflammatory and anti-rheumatic agents. moreover Compound (+)-4,9-dihydro-3-methyl-4-[(4-methyl-1-vera (dinyl)-acetylgo-10H-thieno[3,4-bI[1,5]benzodi Azepin-10-one is significantly involved in the cholinergic mechanism May be used in combination with agents to treat disease conditions (e.g. asthma) .

Pharmacological effect The excellent efficacy of telenzevin was demonstrated in anesthetized and naturally breathing guinea pigs (i,v). , - injection and i, t, single infusion injection) and guinea pigs without anesthesia (p, o, - administration) was detected in a model of acetylcholine-induced bronchial spasm.

Acetylcholine-induced bronchial spasm in anesthetized naturally breathing guinea pigs. i, v, - Effect of administered telenzevin Test method: pharmacodynamics on internal sensitive receptors and guinea pig respiration Method for simultaneous recording of toxic and toxic effects (U, K11ian, E, MQl!er, E, ch, Dittmann and J, Hamacher, Arzne i m, -Forsch, 28, 1699-1708, 1978) Guinea pig : Pirbright White, Inter 7 Out Interfauna Tuttlingen, 350-450g s anesthesia; As an aqueous solution of 1.2 g/kg i, p, 12.5% of ethyl urethane I/tan.

record: Breathing rate depiction device: Maximum flow velocity of breathing air during exhalation (Vmax, "pea k flow-), respiratory volume (TV) dose: μmol/kg i, v, (±)-tetra dissolved in +0.9% NaCl2- solution Ren (Bin 0.03 0.05 0.1 1 5 (÷) - Terenzebin 0. 03 0.05 0.1 0.5 1(-)-Telenzevin 0.1 1 5 10 30 Acetylcholine as subasmogen 0.2-02-0-31z/kg i; v,, Test course dissolved in 0.9% NaCl2-solution: Control spasticity - 10 minutes, substance application 0 minutes, test spasticity +2. +lO1+20+30.　 +60 minutes.

evaluation: of telenzevin relative to the measured control (mean and standard error of the mean, n=10). Recording of effects and then decreases in Vmax and TV due to acetylcholine Calculation of bronchospasmodic activity as a percentage inhibition by time-effect curves. Time Average bronchial spasm during the observation time (0-60 minutes) from the original area of the drop curve Determination of activity by calculation of dose-effect curves and reading of 1h-ED50-values . Determination of dose-effect curves of bronchospasmodic activity at 60 minutes and ED5Q- Reading the value.

result: (±)-Terenzevin and (+)-Terenzevin are caused by acetylcholine. O-03-1 umol/kg depending on dose and time i, v.

inhibited at significantly lower doses. This effect was significant despite i,v,-administration. It appears slowly at 10-30 μmol/kgi, v, and reaches its maximum value at 10-30 μmol/kgi, v. this time The descent curve can be compared to that of both different teleazepine forms.

Tables 1 and 2 show that the total observation time for 0-SO minutes is 60 minutes p, a, The effect of telenzevin was described by a dose-effect curve of mean activity at time points. child The ED5Q-values derived from this are shown in Tables 38 and 4.

Table 1 (±)-9(+)- and (-)-Telenzebi during the entire observation time (0-60 min) The average bronchospasmolytic activity of the acetylcholine-induced spasticity test compared to control spasticity Maximum flow rate of respiratory volume during spasticity (Vmax)μ 薗lAg1. v, 0.03 0.05 0.1 0.5 1 5 10 30 (±)-Telenze Bottle 7±3 22±3 61±8 81±4 75±3 (-)-Telenzo bottle 2±l 17 Sat 3 65±4 79±2 89±3 (±)-Te1 Nzebin 7±3 26±4 68±9 84±4 86±2 TV (+)-t 17f4 25t5 62t5 92f3 a5t3(-)-Telenzevin 0±2 20±5 74±4 87±2 98±3 Table 2 (±)-0(+)- and (-)-telensevin air at 60 min p,a. Bronchial antispasmodic activity in acetylcholine-induced test spasticity compared to control spasticity Maximum flow rate of respiratory volume (Vmax) and respiratory flow rate μ1lIol/k during offspring gi, v, 0.03 0.05 0.1 0.5 1 5 10 30 (±) - Telenzevin ll±4 25±3 70±9 82±5 80±4(-)-te Lenzevin 1thl 18±3 77±5 77±3 88±4 (±)-Tele Nzebin 12±6 32±5 78±11 85±5 91±3 TV (+) -Terenzevin 23*7 39*7 64*7 100*4 88*4 (-) -Telenzevin -3±3 22±5 88±6 89±3 94±3 Table 3 E of the average bronchospasmolytic activity of (±)-, (+)- and (-)-telensebin D5Q value.

ED5 (1 μmol/kg i, v, (±)-Terenzevin (+)-Terenzevin (-)-Terenzevin TV O ,070,082,5 Table 4 (±)-, (+)- and (-)-te1/nzevin at 60 min p,a. ED5Q value of bronchial spasmolytic activity.

EDH μmol/kg i, v.

(±)-Terenzebin (÷)-Terenzebin (-)-Terenzebin Vmax O,0B 0.07 3.2TV O,070,072,0 Anesthetized; on acetylcholine-induced changes in pulmonary function coefficients in guinea pigs (± ) - Effects of telenzevin (intratracheal i, t,) Test method: Anesthetization; Small animal complete volumetric device (Method) for guinea pigs nach U, He1nrich and A, Wilhalm, in bga-S chriften 5/8C255-266 pages, MMW-Verlag+ 19 8 guinea pigs: Pirbright White, Interfauna (Interfauna Tuttlingen), 290-350g, male hemp Drunkness: Ethyl urethane 1.2g/kg i, p, as a 12.5% aqueous solution.

record: Inserted into the natural tract in the volumetric depiction; the flow rate of respiratory air through the tracheal catheter and Measurement of respiratory volume and intrapleural pressure using an esophageal catheter inserted into the natural meatus : 0.9% NaCl2 + 0.1% Tween 80 0, (± ) - Telenzepine i, L, 0.001, 0-01.0.1 and 1μ city o1/ kg as a spastic agent, 0°18% Achlo, 9% Na (12 solutions of ultrasound Administered by nebulization.

Test progress: Control spasticity - 10 minutes, substance application 0 minutes, test spasticity +5. +30 minutes.

evaluation: Amdur before and at the maximum of spasticity and in the formation of the difference Conductance from automatically recorded parameters by and Mead's method (permeability of the respiratory tract for air, corresponding to the reciprocal of the respiratory tract resistance) and complete Calculated measurement of lung distensibility, inhibition of spasticity after substance administration compared to control. Calculation of inhibition rate, dose-effect curve and calculation of ED5Q value of this antispasmodic activity.

result: (±)-Telenzebin inhibits acetylcholine-induced conductance and completion. Depending on time and dose, a wide range but significantly lower 0°0 It is inhibited in the dosage range of 01-1 μmol/kg i, t. This effect lasts for 5 minutes, 30 minutes p, a, is more significant than a.

Table 5 shows the dose-effect curve of (±)-terenzebin 5-30 min p, a, bronchial The antispasmodic effect was described. The EDBo values derived from this are summarized in Table 6.

Table 5 The bronchospasmolytic activity of (±)-telenzepine at 5-30 min p,a was significantly different from control spasticity. Conductance and compression in acetylcholine-induced test spasticity compared (X±SEM, N-10).

μmol/kg i, t, 0.001 0.01 0.1 1 conductance 12±3 62±10 46±10 65±9 Compliance 5±1 50 ±9 34±10 57±9 Conductance 20±5 51±9 54±7 84±2 Compliance 13±3 49±9 51*9 89±4 Table 6 i, t, EDQQ value of bronchial antispasmodic effect of (±)-telenzevin by injection ED50 μmol/kg i, t.

5 minutes p, a, 30 minutes p, a.

Conductance 0.05 0.03 Humpriance 0.3 0.03 Regarding acetylcholine-induced respiratory depression in unanesthetized guinea pigs, p. o, administered t; Effects of (±)-telenzepine experimental method: R, Beu+oe, U, Ki 1 fan, NJolassa, K , Mussler, Atemv, -Lu Mott's bronchial antispasmodic substance trial Guinea pig as described in “Experience”): Pirbright White, Interfauna (Interfauna Tuttlingen), 250-450g, male , 10 animals per administration and test Recording and evaluation: Measurement of respiratory activity with a thoracograph, from the start of acetylcholine nebulization to the onset of an asthma attack Measurement of the latency time of the test seizure at 30 minutes p,a Confirming the number of animals when the number triples or more; roughly ED5Q reviews from here. Value.

Dose: (±)-Telenzepine p, o, 0. l, 0.3, 1.3.10 and 30 ga ol/kg (4% Methocel) administered with 0.9% NaCl ): Acetylcholine in 0.9% NaCl (ultrasonic nebulization) by inhalation.

result: p,o, dependent on the dose of (±)-telensevin administered, acetylcholine The animal's latency when the resulting test seizure is three times or more compared to the control seizure. The numbers are listed below.

From this, the approximate EDso O,7 (0,3-1°795%-Tnt , ) μmol/kg p, o, were obtained.

Receptor affinity test: (±)-4,9-dihydro-3-methyl-4-[(4-methyl-1-piperazine )-acetyl] l0H-cheno [3,4-b] [1,51 benzodiase Pin-10-one (telenzepine, compound 2 in Table 7 below) and its conformers [(+)-image reader compound l.

(=) - enantiomer - muscarinic Mx of compound 31 (ganglion type gangoli onler　Type) receptor and M2 (cardiac type) receptor r　Typ) The affinity for the receptor was examined by the following method.

Method l: Electrically stimulated vas deferens of a rabbit in an organ bath (Eltze, M., 198 g , Submitted for publication in Europe, J, Pharmacol,) Organ bath (10 mff, 31°C, gas treatment with carbodiene, suspending 0.75 g of organs) In the isolated rabbit vas deferens fragment (male, veisse Neuseel) aender, 2.5-3.5 kg) using electrical stimulation (HSE-stimulator; bath water Isometric contraction under a plate-shaped Pt electrode 1 cm below the surface (HSE-force recorder, K-3Q ; Kipp and Zonen, BD-9 recorder). 30 minutes equilibration After oxidation, it is Similar McN-A-343 (l O-7-2X) for each of the 8 organ fragments A cumulative dose-effect curve of 10-'M) was established. With three types of contrast curves, A constant concentration of agonist per organ fragment (e.g. 5X10-7.10-6. 3 x 1 0-6. l　O-6 or 3X10-5M) was administered, and the effect After stabilization of the fruit, the high concentration of the antagonist to be tested is added. Culture medium used The nutrient solution had the following composition (mM): NaCQl 18, KCQ 4.7. CaCQ2x2Hz02.5. Mg5O4X7H200,6,KH2PO41, 2, NaHCO325,0 and glucose 1l-1oa2-adrenoceptor For the blockage of yohimbine, the culture medium additionally contains 10-6 M of yohimbine.

Method 2: Electrically stimulated rat left atrium (Eltze et al., 1985, E urop, J, Pharmacol, 122.211224) Organ bath (10ra Q, Tyrode culture solution (Tyrode), 31°C, gas treatment with carbodiene, organ The isolated left atrium of a rat (male, 250-350 g) Electrical stimulation (HSE-stimulator; a disc-shaped Pt electrode at the bottom of the bath and the water surface of the bath Ring-shaped Pt electrode immersed in lower lam; isometric under 7V, 3ms, 2Hz) Sexual contraction (HSE-force recorder, K-30; Watanabe Linear Record Corder Mark 5). After 30 minutes of equilibration, the van For each of the four organs, the technique described by Rossum (1963) and similar carbachol (10-8-10''6M.

Cumulative dose-effect curves (up to 1O-5 or to-4M in the presence of antagonist) Set t；゛. The substance to be tested was added to the organ bath 20 minutes before administration of carbachol. added.

The break between individual dose-effect curves is 30-45 minutes.

The Tyrode's culture solution used had the following composition (mM). NaC11130 , KCQ2. O,CaC(12X2H201,8,Mg(,+22x6H200 ,98,NaHCOsl 2.0. NaH2PO4 and glucose:I-su%/I= Trade 5.6° pA2-billion (molar dissociation constant of competitive antagonist-receptor complex) number) is measured by line regression in a Schild-Plot. is determined: pA2=-1Og[B/(x-1)]+(Arunlaksh ana and 5child, 1959) The following Table 7 shows the 2-values for p of substances. t;. At this value, the increase in the regression degree for the theoretical competitive antagonism is 1.0. 0 (Tallarida et al., 1979).

Table 7 (±)-4,9-dihydro-3-methyl-4-[(4-methyl-1-piperazine )-acetyl]-10H-cheno[3,4-b][1,5]benzodia Zepin-10-one (telensevin, -compound 2) and its conformer [(+ ) - Image reader compound 1. Ml and M2 receptors of (-)-enantiomer-compound 3] affinity for Substance Battle 1 - Seven Butters (Gangolion Proof Rer) M2-1/ Seven Butters (cardia+er) Rabbit vas deferens Rat left atrium pA2±SEM n pA2±SEM n Compound 1 9.12±0.08 7- 18 7.67±0.08 15-20 Compound 2 8.86±0.06 20 7.32±0.09 6-11 Compound 3 6.98±0.14 11-18 6 ．． 12±0.06 11-15 Note: Van Rossuw J, M, 1963. Arch, int, Pharm acodyn, 143.299° Eltze, M, et al, +1985+Europ, J, Phartoac ol, 112+211°A, runlakshana O, and H, O, 5c hild, 1959. Br, J, Pharmacol, 14.48 Tallarida R, J, et at, J979. Life Sci, 25 , 637° Eltze M, , 1988. Submitted for pu blification tn Eur.

p, J, Pharmacol.

Anti-heel ulcer properties and selective inhibition on degenerated 5hay-Ratte Test of action Compound (+)-4,9-dihydro-3-methyl-4-[(4-methyl-1-pipe Radinyl) acetyl 1-10H-cheno[3,4-b][1,5]benzodi The corresponding (-)-mirror of azepin-10-one (compound l in Table 8 below) Excellent gastroprotective effect compared to the stereoisomer (-compound 3) and the racemate (-compound 2) and the gastric juice secretion inhibiting effect can be detected in experiments on modified Seyrats. next Table 8 shows that intravenous administration of degenerated Ceira rats caused lesion formation and acid content. The effect of said compounds on secretion was shown.

Table 8 Gastroprotective effect: Blocking acid secretion Rat gastric lesion index or HCff secretion in treated groups is reduced by almost 50% compared to the control group.

*Inhibition by 3mg: 46% methodology Ulcer induction was performed using starved rats (female, 180-200 g, per high-grid cage). 4 animals) were treated with pyloric ligation (diethyl ether anesthesia) and acetylsalicyl 1210 The test was performed by oral administration at 0 mg/l Oml/kg. The substance to be tested is intravenous Administered intravenously (1 ml/kg) immediately after pylorus ligation. Wound closure by Michelle Kuri This was done using a tap.

After 4 hours, the animals were sacrificed by atlantolateral dislocation under ether anesthesia, and the stomachs were removed.

The stomach is incised along the greater curvature, the amount (volume) of gastric juice secreted in advance is measured, and then The HCQ content (titration with caustic soda solution) was measured on a cork plate. I pasted it on. III present at 10x magnification using a stereo microscope The number and size of tumors (diameter) were measured. Severity (according to the following point scale) ) and the results from the number of tumors are used for the individual lesion index.

Point scale: No tumor Tumor diameter 0.1-1.4mm 1 1.5-2.4mm 2 2.5-3.4mm 3 3.5-4.4mm 4 4.5-5.4mm 5 >5.5mm 5 each compared with the control group (-100%) as a measure for antitumor efficacy. After treatment, the group mean lesion index reduction was used. This ED5 ° decreased mean lesion index or HCQ secretion by 50% compared to control. represents the dose given.

Orchid l□□llll&　PCT/EPa8101173-1--1 Shizuka-111 PCτ /ΣPea104173-11-^-maw”LPCT/EP88.’0117 3 International search report

Claims (10)

[Claims] 1. 4,9-dihydre for the production of medicaments for the treatment and prevention of bronchial diseases rho-3-methyl-4-[(4-methyl-1-piperazinyl)acetyl]-10H -thieno[3,4-b][1,5]benzodiazepine-10-one and its drugs Use of physically acceptable salts. 2. (+)-4,9 for manufacturing medicines for the treatment and prevention of bronchial diseases -dihydro-3-methyl-4-[(4-methyl-1-piperazinyl)acetyl] -10H-thieno[3,4-b][1,5]bennodiazepin-10-one and Use of pharmacologically acceptable salts. 3. 4,9-dihydro-3-methyl-4- for the treatment and prevention of bronchial diseases [(4-methyl-1-piperazinyl)acetyl]-10H-thieno[3,4-b ][1,5]benzodiazepine-10-one and its pharmacologically acceptable salts use. 4. (+)-4,9-dihydro-3-methylene for the treatment and prevention of bronchial diseases Ru-4-[(4-methyl-1-piperazinyl)acetyl]-10H-thieno[3 ,4-b][1,5]benzodiazepine-10-one and its pharmacologically acceptable Use of sexual salts. 5.4,9-dihydro-3-methyl-4-[(4-methyl-1-piperazinyl) Acetyl]-10H-thieno[3,4-b][1,5]benzodiazepine-10 Method for producing (+)- and (-)-conformers of -one (compounds of formula I) In Formula I: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) ▲ Mathematical formulas, chemical formulas, tables, etc. There is a conformer of the compound of formula II [wherein the configuration unit and X represents a leaving group] The diastereomeric mixture III thus obtained was separated and optically analyzed. Characterized by separating the conformational unit of Compound 1 from the pure diastereomer 4,9-dihydro-3-methyl-4-[(4-methyl-1-piperazinyl)acetate [chill]-10H-thieno[3,4-b][1,5]benzodiazepine-10-o A method for producing (+)- and (-)-conformers of 6. 6. The method according to claim 5, wherein R is an isopinocampheyloxymethyl group. 7. (+)-4,9-dihydro-3-methyl-4-[(4-methyl-1-pipera [dinyl)acetyl]-10H-thieno[3,4-b][1,5]benzodiazepi ion-10-one and its salts. 8. Intermediate of formula III according to claim 5 [wherein R represents the one according to claim 5] and its salt. 9. Intermediate of formula III according to claim 5 [wherein R represents the one according to claim 6] and its salt. 10. (+)-4,9-dihydro-3-methyl-4-[(4-methyl-1-pipe Radinyl)acetyl]-10H-thieno[3,4-b][1,5]benzodiaze Pin-10-one and/or a pharmacologically acceptable salt thereof.